EP1054682B1 - Utilisation de l'hyperforine et d'extraits en contenant pour le traitement et la prophylaxie des maladies liees a la demence - Google Patents

Utilisation de l'hyperforine et d'extraits en contenant pour le traitement et la prophylaxie des maladies liees a la demence Download PDF

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Publication number
EP1054682B1
EP1054682B1 EP99932474A EP99932474A EP1054682B1 EP 1054682 B1 EP1054682 B1 EP 1054682B1 EP 99932474 A EP99932474 A EP 99932474A EP 99932474 A EP99932474 A EP 99932474A EP 1054682 B1 EP1054682 B1 EP 1054682B1
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EP
European Patent Office
Prior art keywords
hyperforin
treatment
dementia
extracts
prophylaxis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP99932474A
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German (de)
English (en)
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EP1054682A2 (fr
Inventor
Shyam Sunder Chatterjee
Clemens Erdelmeier
Michael NÖLDNER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Willmar Schwabe GmbH and Co KG
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Dr Willmar Schwabe GmbH and Co KG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the invention relates to the use of hyperforin and hyperforin-containing extracts from Hypericum perforatum L. (St. John's wort) for the manufacture of a medicinal product for the treatment and prophylaxis of dementia diseases such as Alzheimer's disease.
  • the phloroglucin derivative Hyperforin of the following structural formula is one of the main ingredients of St. John's wort. Since the substance is chemically unstable, its content decreases when the fresh plant dries. With quick drying and under gentle conditions, Hyperforin is still found in high concentration in the St. John's wort drug, which is comparable to the content of fresh plants.
  • Hypericum extracts have been used for treatment for many years used by depression and psychovegetative disorders (see Linde et al., BMJ, Vol. 313, pp. 253-258, (1996)).
  • DE-PS 196 19 512 is a process for the production of Hypericum extracts are described that have a stable hyperforin content of at least 2% included.
  • Hypericum dry extracts and Processes for their preparation are known to be deficient in hypericin are, but have a higher content of Hyperforin than that vegetable raw material. These extracts have one strong serotonin-antagonistic effect, and they become Making psychovegetative and antidepressant more effective Medicines used. These extracts are used for treatment of anxiety disorders, nervous agitation, migraines, gastrointestinal disorders and vomiting.
  • the a Hypericum extract alone or in combination with other substances contain a variety of uses in medical and cosmetic field described. Known are especially antiviral and antibacterial Effects.
  • WO 97/22354 describes the use of Hypericum extracts for the treatment of viral diseases, especially known from HIV, while in Russian Patent specification RU-C1-2 031 645 antibacterial effects and the use of ointments containing Hypericum extract Prevention of transmissible during sexual intercourse Diseases are described.
  • Hyperforin and hyperforin-containing extracts from Hypericum perforatum L are significantly influenced by hyperforin and hyperforin-containing extracts from Hypericum perforatum L.
  • Such an effect has so far been described neither for hyperforin nor for extracts containing hyperforin and was also not to be expected on the basis of the pharmacological and clinical effects known to date.
  • an influence on the memory performance by a hyperforin-rich Hypericum extract and by Hyperforin itself was found for the first time. Hyperforin and extracts containing hyperforin can thus be used for the therapy of neurological diseases associated with dementia.
  • Dementia is a significant decrease in intellectual performance, which appears as a decrease in memory and thinking ability and is associated with an impairment of personal activities in daily life.
  • Large autopsy statistics and clinical-epidemiological studies show that neurodegenerative diseases are the most common cause of dementia with about 60%. This is followed by the so-called vascular dementia forms in about 20% of the cases and other causes in another 20% (cf. Rösler et. Al., Schwier. Med. 114 , pp. 351-356 (1996)). To date, there is no generally accepted treatment method for dementia, so treatment must be limited to improving clinical symptoms.
  • Alzheimer's dementia or Alzheimer's disease, is a gradual illness that is characterized by initial forgetfulness, increasing memory disorders and loss of other cognitive skills. It ends with the complete mental decline and loss of personality of the patient. A satisfactory causal therapy for this disease has not been available to date (see K. Mendla, "Alzheimer's Disease: New Approaches in Pharmacotherapy", Pharm. Science 141 , pp. 351-356 (1996)).
  • Alzheimer's dementia is treated with acetylcholinesterase inhibitors to increase the amount of acetylcholine available in the brain. This treatment leads to a number of undesirable side effects which do not permit permanent therapy (cf. Shvaloff et al., Psychopharmacology Bulletin, Vol. 32, pp. 343-352 (1996)).
  • the invention is therefore based on the object anti-dementia substances and such substances provide compositions containing less Side effects than previously for this indication used drugs.
  • the invention thus relates to Use of Hyperforin and extracts containing Hyperforin of St. John's wort for the manufacture of a medicinal product Treatment and prophylaxis of dementia, especially Alzheimer's disease, vascular dementia and of mixed forms of dementia.
  • the extract preferably contains at least 2% by weight hyperforin.
  • the hyperforin is preferably by adding a stabilizer stabilized.
  • Hyperforin and hyperforin Extracts a causal therapeutic starting point to show, because surprisingly found was that Hyperforin and the extracts mentioned were potent Protein kinase C ⁇ stimulators are. This protein kinase C ⁇ activates ⁇ -secretase, which in turn causes it to develop of the pathogenic amyloid A ⁇ prevented.
  • a special Advantage of Hyperforin and extracts containing Hyperforin thus lies in the fact that this is not only targeted at education of amyloid A ⁇ , but also those at Dementia, especially Alzheimer's, common accompanying psychiatric symptoms such as anxiety, Depression and other psychovegetative disorders are effective can fight.
  • a hyperforin containing usable according to the invention Extract was obtained as follows:
  • Extracts were under stirring, nitrogen atmosphere and Sunscreen in 3 liters of n-heptane saturated with methanol was solved.
  • the extract solution obtained was then once with 1.5 l of methanol saturated with n-heptane, and three times with one liter of the same solvent shaken out.
  • the methanol phases were combined and at a water bath temperature of maximum 45 ° C on Rotary evaporator brought to dryness. in the Vacuum drying oven was left overnight at room temperature post-dried. This gave 20.14 g of methanol phase.
  • the total amount of methanol phase was dissolved in 100 ml of methanol.
  • the stock solution thus obtained was used for preparative high-pressure liquid chromatography (HPLC): it was degassed in an ultrasonic bath for about 2 minutes, stored in an amber glass under a nitrogen atmosphere at ⁇ 18 ° C. and subjected to preparative HPLC. 3.7 ml of the stock solution were used for each preparative HPLC separation, which corresponds to a substance amount of 745 mg.
  • the conditions of preparative HPLC were as follows: Eluens 88 vol .-% methanol, pure Detection 270 nm Flow 90 ml / min. pillar Eurospher 100-C18, 7 ⁇ m, ID 32 mm.
  • the Hyperforin peak was collected from every single preparative separation.
  • the HPLC eluates containing Hyperforin were initially stored at - 18 ° C. Then they were combined and rapidly concentrated on a rotary evaporator with a maximum of 45 ° C water bath temperature, with light protection and nitrogen gasification of the storage vessel. These concentrates were rinsed into brown glasses with the help of methanol and stored at -18 ° C. under a nitrogen atmosphere until finally combined. After removal of the methanol and high vacuum drying, 9.4 g of hyperforin were obtained, which was characterized by UV, IR and 1 H-NMR and 13 C-NMR spectra.
  • Extract containing hyperforin was the so-called "conditioned avoidance" model selected.
  • This model uses a closed plastic cage, the "conditioned avoidance box", used in the middle through a partition into two equal chambers or Compartments is divided. In the middle of the partition there is a door through an automatic Control can be opened and closed.
  • the floor both chambers consist of an electrically conductive Grating. There is one on the walls of each chamber Lamp and a loudspeaker, via the light and sound signals can be delivered.
  • a single rat is placed in the right one for training Compartment of the box set, the door of the partition remains closed. After the rat sticks to the 10 minutes accustomed to a new environment, an automated one begins Program with opening the door. Appears after 20 seconds a combined tone and light signal in the Chamber in which the rat is staying (conditioned stimulus). Despite the stimulus, the rat stays in the Chamber, followed by a 3 second current stimulus over the Bars (unconditioned stimulus). Then starts a new cycle. Changes the rat before or during the conditioned stimulus in the opposite chamber, avoids the current stimulus, and the new cycle begins in the other chamber. In total, the rat must have 40 such Complete passes a day. Repeat this procedure in the same way on seven consecutive days and way. This is followed by a break of 10 days, in who are neither treated nor trained. On the 17th day of the trial the animals are put into the box one last time, but with the difference that there are no more current stimuli be applied.
  • the rats learn that the current stimulus by changing the compartments can avoid (avoidance behavior). Substances the Improving learning or memory functions lead to one faster learning of avoidance behavior and thereby to a lower number of electric shocks.
  • the graphs shown in Fig. 1 give the number correct change of test animals from one compartment in the other from the 1st to the 7th day and - after ten days Break - on the 17th day again, both for untreated Laboratory animals as well as laboratory animals that are 25 mg / kg or 50 mg / kg Hypericum extract p.o. administered have got, and such experimental animals that 1.25 daily or 2.5 mg / kg pure hyperforin p.o. get administered to have. It is striking that pure Hyperforin less is effective than the Hypericum extract in a dose of 50 mg / kg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (3)

  1. Utilisation d'hyperforine et d'extraits contenant de l'hyperforine, de l' Hypericum perforatum L . (millepertuis), pour la préparation d'un médicament pour le traitement et la prophylaxie de maladies démentielles, en particulier de la maladie d'Alzheimer, de la démence vasculaire et de formes mixtes de démence.
  2. Utilisation selon la revendication 1, caractérisée en ce que l'extrait contient au moins 2 pour cent en poids d'hyperforine.
  3. Utilisation selon la revendication 1 ou 2, caractérisée en ce que l'hyperforine est stabilisée par l'addition d'un stabilisateur.
EP99932474A 1998-02-13 1999-02-04 Utilisation de l'hyperforine et d'extraits en contenant pour le traitement et la prophylaxie des maladies liees a la demence Expired - Lifetime EP1054682B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19805946 1998-02-13
DE19805946 1998-02-13
PCT/EP1999/000730 WO1999040905A2 (fr) 1998-02-13 1999-02-04 Utilisation de l'hyperforine et d'extraits en contenant pour le traitement et la prophylaxie des maladies liees a la demence

Publications (2)

Publication Number Publication Date
EP1054682A2 EP1054682A2 (fr) 2000-11-29
EP1054682B1 true EP1054682B1 (fr) 2001-08-29

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EP99932474A Expired - Lifetime EP1054682B1 (fr) 1998-02-13 1999-02-04 Utilisation de l'hyperforine et d'extraits en contenant pour le traitement et la prophylaxie des maladies liees a la demence

Country Status (9)

Country Link
US (1) US6322824B1 (fr)
EP (1) EP1054682B1 (fr)
JP (1) JP2002539070A (fr)
AT (1) ATE204759T1 (fr)
AU (1) AU754679B2 (fr)
CA (1) CA2320154A1 (fr)
DE (1) DE59900222D1 (fr)
ES (1) ES2162520T3 (fr)
WO (1) WO1999040905A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1056705B1 (fr) * 1998-02-13 2003-10-29 Dr. Willmar Schwabe GmbH & Co. KG Sels d'hyperforine stables, leur procede de preparation et leur utilisation pour le traitement de la maladie d'alzheimer

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025824A2 (fr) * 1998-11-04 2000-05-11 Dr. Willmar Schwabe Gmbh & Co. Preparations stables contenant de l'hyperforine
US7205008B2 (en) * 2000-03-15 2007-04-17 Proteotech, Inc. Methods of treating Alzheimer's disease and other amyloidoses using Hypericum perforatum and derivatives thereof
DE10131641A1 (de) * 2000-12-22 2002-06-27 Schwabe Willmar Gmbh & Co Verbesserter und stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und Verwendung als topisches Arzneimittel
DE10213571A1 (de) * 2002-03-26 2003-10-23 Lichtwer Pharma Ag Pflanzenextrakte und deren Anwendung
ITMI20020871A1 (it) * 2002-04-23 2003-10-23 Indena Spa Derivati alogenati dell'iperforina loro uso e formulazioni che li contengono
ITMI20020872A1 (it) 2002-04-23 2003-10-23 Indena Spa Derivati dell'iperforina loro uso e formulazioni che li contengono
WO2005095983A1 (fr) * 2004-03-04 2005-10-13 Bayer Healthcare Ag Diagnostics et therapies de maladies associees a la proteine kinase c, gamma (prkcg)
DE202009018261U1 (de) 2009-12-23 2011-11-09 Finzelberg Gmbh & Co. Kg Johanniskrautextrakte zur Behandlung von neurodegenerativen Erkrankungen
WO2011076867A2 (fr) 2009-12-23 2011-06-30 Finzelberg Gmbh & Co. Kg Extraits végétaux pour le traitement de maladies neurodégénératives
WO2012025609A1 (fr) 2010-08-27 2012-03-01 Finzelberg Gmbh & Co. Kg Extraits végétaux de sideritis et leur utilisation pour augmenter les performances cognitives

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733332B2 (ja) * 1985-11-19 1995-04-12 富山化学工業株式会社 痴呆症状改善・治療剤
JPH04210642A (ja) 1990-12-10 1992-07-31 Kao Corp 抗痴呆剤
DE4239959A1 (de) 1992-11-27 1994-06-01 Schwabe Willmar Gmbh & Co Johanniskraut-Trockenextrakt, Verfahren zu seiner Herstellung und seine Verwendung
DE19619512C5 (de) * 1995-09-29 2006-04-20 Dr. Willmar Schwabe Gmbh & Co. Kg Stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und pharmazeutische Zubereitungen
DE19646977A1 (de) 1995-09-29 1998-01-15 Schwabe Willmar Gmbh & Co Stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und pharmazeutische Zubereitungen
US6117855A (en) * 1996-10-07 2000-09-12 Merck Sharp & Dohme Ltd. Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent
US5733926A (en) * 1996-12-13 1998-03-31 Gorbach; Sherwood L. Isoflavonoids for treatment and prevention of alzheimer dementia and reduced cognitive functions
AU3886200A (en) * 1999-03-15 2000-10-16 Proteotech, Inc. Methods of treating alzheimer's disease and other amyloidoses using hypericum perforatum and derivatives thereof
US6159986A (en) * 1999-11-02 2000-12-12 Altman; David A. Compounds and therapy for resisting memory loss in humans

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1056705B1 (fr) * 1998-02-13 2003-10-29 Dr. Willmar Schwabe GmbH & Co. KG Sels d'hyperforine stables, leur procede de preparation et leur utilisation pour le traitement de la maladie d'alzheimer

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CA2320154A1 (fr) 1999-08-19
WO1999040905A2 (fr) 1999-08-19
ATE204759T1 (de) 2001-09-15
AU3252699A (en) 1999-08-30
AU754679B2 (en) 2002-11-21
EP1054682A2 (fr) 2000-11-29
JP2002539070A (ja) 2002-11-19
US6322824B1 (en) 2001-11-27
WO1999040905A3 (fr) 1999-09-23
ES2162520T3 (es) 2001-12-16
DE59900222D1 (de) 2001-10-04

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